Shigella flexneri is the primary cause of childhood dysentery in the developing world and a major cause of travelers' diarrhea in the developed world. While significant resources have been dedicated to developing effective enteric vaccines, a viable vaccine against shigellosis has yet to be realized. As a novel approach we have identified two higher conserved and required proteins of the type III secretion system apparatus (TTSA) as protective antigens against Shigella spp infections. We have demonstrated that, when administered intranasally as a solution in the presence of an adjuvant, the invasion plasmid antigens IpaD and IpaB protect mice against a lethal challenge by S. flexneri and the heterologous S. sonnei using the mouse lung model. Furthermore, in an effort to simplify formulation and reduce production costs, we constructed an IpaD-IpaB fusion protein (DB Fusion) which is also protective when administered intranasally and intradermally against S. flexneri, S. sonnei and S. dysenteriae. Within this proposal we intend to develop a tablet formulation of this Ipa-based vaccine using the novel dmLT as an adjuvant for sublingual (SL) immunization. These sublingual tablets dissolve rapidly under the tongue but will be more stable than an aqueous form of vaccine and can be self-administered. We hypothesize that in addition to increased stability and ease of self-administration, this DB Fusion+dmLT tablet vaccine will provide homologous and heterologous protection against Shigella spp. To test this hypothesis, the specific aims of this investigation are to: 1. Formulate the DB Fusion into a tablet for sublingual administration and assess the protein stability within the tablet; 2. Determine the immunogenicity and protective efficacy of the tablet vaccine via SL route. We believe that the R21 mechanism is appropriate for this project because the high impact that such a novel formulation would have on worldwide public health. We have preliminary data suggesting the DB Fusion can be converted to a sublingual tablet, however, their stability and their protective efficacy in such a form remains unknown. Should this formulation be successful, we will have a stable vaccine that does not require a needle, does not require a cold-chain and does not require medical personal for administration.